Publications by authors named "K Steindl"
While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder.
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- This study identifies a new type of autosomal recessive intellectual disability linked to genetic variants in the GTF3C3 gene, which is essential for proper RNA polymerase III activity.
- Researchers employed various methods, including exome sequencing and Drosophila models, to analyze the effects of GTF3C3 variants found in twelve affected individuals from seven families.
- The results showed that the variants lead to significant functional losses in the gene, correlating with symptoms like intellectual disability, motor issues, seizures, and brain structure abnormalities.
Hydrocephalus and Dandy-Walker malformation are amongst the most common congenital brain anomalies. We identified three consanguineous families with both obstructive hydrocephalus and Dandy-Walker malformation. To understand the molecular basis of these anomalies, we conducted genome-wide sequencing in these families.
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- Zinc and RING finger 3 (ZNRF3) regulates Wnt/β-catenin signaling, crucial for brain development, but germline variants have not been linked to neurodevelopmental disorders (NDDs) before.
- Researchers found 12 individuals with ZNRF3 variants, noting a correlation between specific mutations and NDD phenotypes, especially those affecting brain size.
- Structural modeling and functional assays revealed that missense variants linked to larger brain size enhanced Wnt signaling, while a variant causing smaller brain size reduced it, indicating different mechanisms at play in NDDs related to ZNRF3 mutations.
While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis.
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